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PDBsum entry 6slg
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References listed in PDB file
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Key reference
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Title
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Discovery of a potent and selective oral inhibitor of erk1/2 (azd0364) that is efficacious in both monotherapy and combination therapy in models of nonsmall cell lung cancer (nsclc).
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Authors
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R.A.Ward,
M.J.Anderton,
P.Bethel,
J.Breed,
C.Cook,
E.J.Davies,
A.Dobson,
Z.Dong,
G.Fairley,
P.Farrington,
L.Feron,
V.Flemington,
F.D.Gibbons,
M.A.Graham,
R.Greenwood,
L.Hanson,
P.Hopcroft,
R.Howells,
J.Hudson,
M.James,
C.D.Jones,
C.R.Jones,
Y.Li,
S.Lamont,
R.Lewis,
N.Lindsay,
J.Mccabe,
T.Mcguire,
P.Rawlins,
K.Roberts,
L.Sandin,
I.Simpson,
S.Swallow,
J.Tang,
G.Tomkinson,
M.Tonge,
Z.Wang,
B.Zhai.
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Ref.
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J Med Chem, 2019,
62,
11004-11018.
[DOI no: ]
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PubMed id
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Abstract
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The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in
approximately 30% of human cancers, primarily by mutations in the BRAF or RAS
genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as
central nodes within this pathway. The feasibility of targeting the RAS/MAPK
pathway has been demonstrated by the clinical responses observed through the use
of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however,
resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical
utility in overcoming acquired resistance to RAF and MEK inhibitors, where
RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K
melanoma. We describe our structure-based design approach leading to the
discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364
exhibits high cellular potency (IC50 = 6 nM) as well as excellent
physicochemical and absorption, distribution, metabolism, and excretion (ADME)
properties and has demonstrated encouraging antitumor activity in preclinical
models.
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